Heroin dependence has become a public health problem with increasing morbidity and mortality. The pre-clinical animal literature suggests that dysregualtion of the mesolimbic dopamine system is involved in the vulnerability to relapse. However, little is known about mesolimbic dopamine function in humans and its role in heroin seeking behavior. Therefore, the goal of this study is to measure dopamine transmission in the functional subdivisions of the striatum (limbic, associative, and sensorimotor) and to correlate these measures with behavioral data obtained from herion self-administration sessions. The study will use PET and |' lC]raclopride with a psychostimulant challenge in order to measure baseline D2 receptor availability and amphetamine-induced dopamine (DA) release in recently detoxified heroin dependent subjects and matched healthy controls. We hypothesize that heroin dependent subjects will have low striatal D2 receptor availability and blunted DA release compared to healthy controls. Heroin dependent subjects will also undergo heroin self-administration sessions in which subjects are given the choice between a low dose of inlranasal heroin and money. DA transmission in the limbic striatum will be correlated with the choice to self-administer heroin and we hypothesize that subjects with the greatest reduction in limbic DA transmission will be more likely to choose heroin in these sessions. We have performed similar studies in cocaine and alcohol dependent subjects, which showed that both disorders are associated with a decrease in baseline D2 receptor availability compared to healthy controls. However, measurements of amphetamine-induced DA release differed between these two diagnostic groups: cocaine dependence was associated with blunted DA transmission in each of the functional subdivisions of the striatum. while alcohol dependence was associated with a loss of DA transmission in the limbic striatum only. Furthermore, we demonstrated that the loss of DA release in the limbic striatum was associated with the choice to self-administer cocaine over an alternative reinforcer. In this application we also present preliminary results in recently detoxified heroin abusers which show low striatal D2 receptor availability and blunting of amphetamine-induced DA release compared lo healthy controls. Continuing this line of research into heroin dependence will serve to further characterize the similarities in mesolimbic and nigrostriatal DA system that occur with dependence lo different drugs and we anticipate that these findings will be important for the development of future treatments for addiction.